Project Summary: The proposed K23 career development award will enable Dr. Lewis to establish an independent program of translational research in computational genomics and congenital heart disease (CHD). To do so, Dr. Lewis, a CHD cardiologist with a background in clinical research, will require training in genomics and bioinformatics. Specifically, his outstanding mentorship team will his guide training in: 1) the genetics of CHD; 2) computational and translational informatics; 3) the design and analysis of genomic studies; 4) research dissemination and career development. In this K23, Dr. Lewis will test the association of damaging genetic variation with decreased ventricular function, as assessed by a core echocardiography lab, in a multicenter cohort of patients with the most morbid form of CHD, hypoplastic left heart syndrome (HLHS). The need for improved methods of risk stratification and the development of novel therapeutics in this population is pressing. While there is increasing evidence that genetic variation plays a role in the development of CHD, the impact of damaging genetic variation on clinical outcomes remains undefined. Because the molecular changes observed during cardiac remodeling in heart failure resemble fetal cardiac development, the same deleterious mutations responsible for HLHS may also predispose patients to ventricular dysfunction. Through this proposal, Dr. Lewis will be the first to assess whether predicted damaging genetic variation is associated with decreased ventricular function in CHD patients. To accomplish this, Dr. Lewis will assemble a multi-center cohort of patients with HLHS through recruitment of local subjects and partnerships with the NIH-sponsored Pediatric Heart Network and Pediatric Cardiac Genetics Consortia. All patients will have, or have previously undergone, whole exome sequencing (WES). Following, Dr. Lewis and his team will collect at last two echocardiograms from each patient performed at standardized times in their clinical evaluation. These studies will be then transferred to a core echocardiography laboratory with extensive experience in the evaluation of ventricular function in the HLHS patient population. Simultaneously, Dr. Lewis will call potentially damaging de novo variants, inherited variants and copy number variants for each patient. The association of damaging genetic variation with ventricular function will then be tested. Given the multifactorial nature of ventricular function, simultaneous collection of clinical data will allow for inclusion of potential confounders in all models. This proposal will enable Dr. Lewis to a) create the largest cohort of HLHS patients with WES data, b) assess the association between genomic data and ventricular function in a CHD population, and c) lay the foundation for a larger R01 proposal. Positive findings from this proposed study have the potential to have far reaching effects on CHD risk stratification and treatment.